Enrichment of kinase fusions in ESR1 wild-type, metastatic breast cancer revealed by a systematic analysis of 4854 patients.

BACKGROUND

Kinase fusions are rare and poorly characterized in breast cancer (BC). We aimed to characterize kinase fusions within a large cohort of advanced BC.

PATIENTS AND METHODS

A total of 4854 patients with BC were analyzed by Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) targeted DNAseq and MSK-Fusion targeted RNAseq during the study time period.

RESULTS

Twenty-seven of 4854 (0.6%) patients harbored fusions: 11 FGFR (five FGFR2, three FGFR3, three FGFR1), five BRAF, four NTRK1, two RET, two ROS1, one ALK, one ERBB2, and one MET. A history of endocrine therapy was present in 15 (56%) of fusion-positive BC; eight of the 15 cases had available pre-treatment samples, of which six were fusion-negative. None of the fusion-positive BC samples harbored ESR1 hotspot mutations. Two patients with acquired LMNA-NTRK1 fusions and metastatic disease received larotrectinib and demonstrated clinical benefit.

CONCLUSION

Kinase fusions in BC are extremely rare, and appear to be enriched in hormone-resistant, metastatic carcinomas and mutually exclusive with ESR1 mutations. The present study expands the spectrum of genetic alterations activating mitogen-activated protein kinase (MAPK) signaling that can substitute for ESR1 mutations in this setting. Molecular testing at progression after endocrine therapy should include fusion testing, particularly in the absence of ESR1 hotspot alterations, in an effort to identify additional therapeutic options which may provide substantial clinical benefit.

Informations de copyright

Copyright © 2020 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.

Déclaration de conflit d'intérêts

Disclosure PR has received honoraria for consulting/advisory board for Novartis, AstraZeneca, Foundation Medicine and institutional research support from GRAIL, Inc. MS has received research funds from Puma Biotechnology, AstraZeneca, Daiichi Sankyo, Immunomedics, Targimmune, and Menarini Ricerche. He is in the scientific advisory board (SAB) of Menarini Ricerche and Bioscience Institute and is a cofounder of Medendi.org. ML has received honoraria for ad hoc advisory board participation from Merck, Astra-Zeneca, Bristol Myers Squibb, Takeda, Lilly Oncology and Bayer, and research support from LOXO Oncology, Merus, and Helsinn Therapeutics. DMH has received personal fees from Chugai Pharma, Boehringer Ingelheim, AstraZeneca, Pfizer, Bayer, Debiopharm Group, and Genentech/Roche, as well as grants from Bayer, AstraZeneca, Puma Biotechnology, and Loxo Oncology, and employment and equity in Eli Lilly. All personal fees and grants are for work outside the submitted work. AD has honoraria from Medscape, OncLive, PeerVoice, Physician Education Resources, Tyra Biosciences, Targeted Oncology, MORE Health, Research to Practice, Foundation Medicine, PeerView, AstraZeneca, Ignyta/Genentech/Roche, Bayer; consulting roles at Ignyta, Loxo/Lilly, TP Therapeutics, AstraZeneca, Pfizer, Blueprint Medicines, Genentech/Roche, Takeda, Helsinn Therapeutics, BeiGene, Hengrui Therapeutics, Exelixis, 14ner/Elevation Oncology, GlaxoSmithKline, Exelixis, Teva, Taiho, Merck, Puma, Merus, Boeringer Ingelheim, PharmaMar, and Bayer. RB has received a grant from Archer, honoraria for advisory board participation from Loxo oncology and speaking fees from Illumina. SC has received honoraria for ad hoc consulting for Eli Lilly, Sermonix, BMS, Paige AI, Context Therapeutics, Revolution Medicine, and Novartis; research support to the institution from Daiichi Sankyo, Novartis, Eli Lilly, Genentech, and Sanofi. JFH has received honoraria from Medscape, Cor2Ed, ClearView Healthcare Partners, Illumina, and Axiom Healthcare Strategies, as well as research funding from Bayer, Eli Lilly, and Boehringer Ingelheim. All remaining authors have declared no conflicts of interest.